Ziemann Mark, Wu Wei, Deng Xiu-Ling, Du Xiao-Jun
School of Life and Environmental Sciences, Deakin University, Geelong, VIC, Australia.
Key Laboratory of Environment and Genes Related to Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Front Genet. 2022 Jun 8;13:921610. doi: 10.3389/fgene.2022.921610. eCollection 2022.
Mitochondrial dysfunction is implicated in the development of cardiomyopathy and heart failure. Transcription of mitochondrial DNA (mtDNA) encoded genes and subsequent protein synthesis are tightly regulated by nuclear DNA (nDNA) encoded proteins forming the nDNA-mtDNA axis. The scale of abnormalities in this axis in dilated cardiomyopathy (DCM) is unclear. We previously demonstrated, in a mouse DCM model with cardiac Mst1 overexpression, extensive downregulation of mitochondrial genes and mitochondrial dysfunction. Using the pre-acquired transcriptome sequencing database, we studied expression of gene sets of the nDNA-mtDNA axis. Using RNA-sequencing data from DCM hearts of mice at early and severe disease stages, transcriptome was performed for dysregulated nDNA-encoded gene sets that govern mtDNA transcription and protein synthesis. To validate gene data, expression of a panel of proteins was determined by immunoblotting. Relative to littermate controls, DCM hearts showed significant downregulation of all mtDNA encoded mRNAs, as well as mtDNA transcriptional activators. Downregulation was also evident for gene sets of mt-rRNA processing, aminoacyl-tRNA synthases, and mitoribosome subunits for protein synthesis. Multiple downregulated genes belong to mitochondrial protein-importing machinery indicating compromised importing of proteins for mtDNA transcription and translation. Diverse changes were genes of mtRNA-binding proteins that govern maturation and stability of mtDNA-derived RNAs. Expression of mtDNA replicome genes was largely unchanged. These changes were similarly observed in mouse hearts at early and severe stages of DCM. Transcriptome revealed in our DCM model dysregulation of multiple gene sets of the nDNA-mtDNA axis, that is, expected to interfere with mtDNA transcription and protein synthesis. Dysfunction of the nDNA-mtDNA axis might contribute to mitochondrial dysfunction and ultimately development of DCM.
线粒体功能障碍与心肌病和心力衰竭的发生发展有关。线粒体DNA（mtDNA）编码基因的转录及随后的蛋白质合成受到由核DNA（nDNA）编码的蛋白质的严格调控，这些蛋白质形成了nDNA-mtDNA轴。扩张型心肌病（DCM）中该轴异常的程度尚不清楚。我们之前在心脏Mst1过表达的小鼠DCM模型中证明，线粒体基因广泛下调且存在线粒体功能障碍。利用预先获得的转录组测序数据库，我们研究了nDNA-mtDNA轴基因集的表达。使用来自疾病早期和严重阶段的DCM小鼠心脏的RNA测序数据，对调控mtDNA转录和蛋白质合成的失调nDNA编码基因集进行了转录组分析。为了验证基因数据，通过免疫印迹法测定了一组蛋白质的表达。与同窝对照相比，DCM心脏中所有mtDNA编码的mRNA以及mtDNA转录激活因子均显著下调。mt-rRNA加工、氨酰-tRNA合成酶和用于蛋白质合成的线粒体核糖体亚基的基因集也明显下调。多个下调基因属于线粒体蛋白质导入机制，表明mtDNA转录和翻译所需蛋白质的导入受损。mtRNA结合蛋白的基因发生了多种变化，这些蛋白控制着mtDNA衍生RNA的成熟和稳定性。mtDNA复制组基因的表达基本未变。在DCM的早期和严重阶段的小鼠心脏中也观察到了类似的变化。转录组分析显示，在我们的DCM模型中，nDNA-mtDNA轴的多个基因集失调，预计这会干扰mtDNA转录和蛋白质合成。nDNA-mtDNA轴功能障碍可能导致线粒体功能障碍，并最终导致DCM的发生发展。
